Potassium ion channels are responsible for the control and maintenance of many physiological responses, and a wide variety of such channels is known The many classes and subclasses of potassium ion channels allow for the development of new chemical entities which specifically allow or impede the passage of potassium ions (K.sup.+) through these channels, thus altering the physiological state of the cell. Compounds which have the ability to modulate the passage of K.sup.+ through a subset of potassium ion channels which is regulated by the concentration of adenosine triphosphate (ATP) are known as K.sub.ATP channel blockers or K.sub.ATP openers, depending on whether they impede or enhance the passage of K.sup.+.
Alteration of potassium ion channel flux causes variations in the excitable state of a number of tissues; open potassium channels allow the membrane potential to come closer to the potassium equilibrium potential, so that the membrane potential is more stable and less likely to fire (Cook, 1990). Potassium ion channels are also associated with the resting potential, and periods of excitability are terminated by these channels. Thus, by modulating the K.sup.+ ion movement through these channels, the ensuing responses may be of therapeutic benefit.
Type II diabetes is an example of a disease that is effectively treated with, potassium ion channel blockers of the sulphonylurea type with relative safety. Such drugs include tolbutamide and glyburide. Ideally these drugs display both rapid onset and short duration of action, thus reducing the risk of chronic hyperinsulinaemia, which is a risk factor for atherosclerosis, and of potentially fatal hypoglycaemic incidents Thus discontinuous exposure appears to be best during long term treatment, because the plasma drug concentration falls below the threshold level during at least part of the night, since desensitisation appears to be associated with the use of high concentrations of and continuous exposure to sulphonylureas (Palmer and Brogden, 1993).
The K.sub.ATP blockers alter the regulation of insulin secretion from pancreatic .beta. cells. This effect results from the fact that the K.sub.ATP channels which maintain the cell membrane resting potential are generally open in resting conditions, but close due to an increase in intracellular ATP following glucose metabolism Depolarisation of the .beta. cell membrane occurs upon closure of these channels. This induces the activation of the voltage-dependent calcium channels, promoting an influx of Ca.sup.2+ into the cells, which facilitates the secretion of insulin from .beta. cells (Gopalakrishnan et al, 1993). These compounds have also been demonstrated to have the ability to alter K.sup.+ channel flux in a variety of non-pancreatic tissues by blocking ATP dependent channels, and may be beneficial for the treatment of other diseases (Robertson and Steinberg, 1990).
The possibilities for therapeutic effects on the heart are numerous, as during diastole the myocardium exhibits a stable high resting membrane potential which is maintained predominantly by K.sup.+ channel currents These currents also regulate the termination of excitation in the myocardium and pacemaker tissue (Cook, 1990). Thus many conditions requiring both emergency care and post-emergency care have the potential to be ameliorated by agents modulating the relevant K.sup.+ channel currents associated with the particular problem Furthermore, under abnormal conditions other parts of the heart, particularly the A-V node and Purkinje fibres, exhibit self excitation, and thus display an intrinsic rhythmic rate of their own which contrasts to the normal rate of contraction. Thus by stabilising the resting membrane potential in these tissues it is possible that these arrhythmias may be controlled
Blockers of the ATP-dependent K.sup.+ channels may prevent or reduce ischaemia-induced ventricular arrhythmias by preventing loss of K.sup.+ through these channels, as demonstrated by the effect of glibenclamide (1 .mu.M) when tested in rat heart stimulated at 5 Hz (Kantor et al, 1987).
Potassium ion channel modulators have demonstrated the ability to induce physiological changes in many tissues The effects of these modulators in the pancreas and the heart have been outlined above, with specific reference to the K.sub.ATP channel blockers In addition, some K.sub.ATP channel openers, such as the non-specific K.sup.+ opener pinacidil, have been found to have vasodilator activity, and are useful as anti-hypersensitive agents (Cohen, 1986).
Neuronal K.sub.ATP channels have also demonstrated an association with transmitter release. The neurotransmitter .gamma.-aminobutyric acid (GABA) is released from the substantia nigra, and this release is mediated via K.sub.ATP channels. K.sub.ATP channel closure induced by sulphonylurea compounds elicits an increase in intracellular Ca.sup.2+ analogous to that described in the pancreas, resulting in the stimulation of GABA secretion (Schmid-Antomarchi et al, 1990).
The potential for the use of K.sub.ATP channel blockers as anti-cancer agents has recently been highlighted with the finding that in cultured MCF-7 human mammary carcinoma cells, reversible cell-cycle arrest arises from the inhibition of K.sub.ATP channels following treatment with K.sub.ATP channel blockers such as Glibenclamide. Cells exposed to Glibenclamide exhibited a concentration-dependent inhibition of cell proliferation, with an IC50 value of 50 .mu.M. Cell populations exposed to Glibenclamide also exhibited a statistically significant accumulation at the G0/G1 phase in cell cycle distribution. (Woodfork et al, 1995).
We have now found a novel family of sulphonyl compounds which have potassium ion channel blocking activity, and which are useful in the treatment of conditions mediated by potassium ion movement through these channels. Such conditions include, but are not limited to, type II diabetes, cardiac arrhythmias ischaemic and hypoxic cardiovascular incidents, and cancers.